Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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4-Pyrrolidino-phmyl-benzyl ether derivatives
The invention relates to racemic or enantiomerically pure 4-pyrrolidino
derivatives,
processes for their preparation, pharmaceutical compositions comprising said
derivatives,
and their use in the prevention and treatment of illness.
More particularly, the present invention relates to compounds of the formula I
R3
Rzs
Rz4 N~Ra
R~.~ \'/
R' \ X~Y \ I Rzz ~ (I)
Rzt
R~'z
wherein
X-Y is -CHZ-CHZ-, -CH=CH- or -CH2-O-;
Rl, Rl'1 and Rl'2 independently from each other are selected from the group
consisting of
hydrogen, halogen, cyano, (Cl-C6)-alkyl, halogen-(Cl-C6)-alkyl, (Cl-C6)-alkoxy
or
1o halogen-(Cl-C6)-alkoxy;
RZi, R2z and Rz3 independently from each other are selected from the group
consisting of
hydrogen and halogen;
Rz4 is hydrogen, halogen or methyl;
R3 is hydrogen;
1s R4 is -CONHRS, -CN or -NHR6;
R5 is hydrogen or (Cl-C3)-alkyl; and
R6 is -C(O)H, -C(O)-(Cl-C6)-alkyl, -C(O)-halogen-(Cl-C3)-alkyl, -C(O)O-(Cl-C3)-
alkyl, -C(O)-NHz or -SOZ-(Cl-C6)-alkyl;
as well as individual isomers, racemic or non-racemic mixtures thereof.
2o Even more particularly, the present invention relates to compounds of the
formula I~
Ra
Rzs
Rz4 N~Ra
/ (Ix~)
\ p \ ~ Rzz ~
~R )~ Rz~
wherein
Rl is halogen, halogen-(C1-C6)-alkyl, cyano, (Cl-C6)-alkoxy or halogen-(Cl-C6)-
alkoxy;
CONFIRMATION COPY
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-2=
Rzy R22' Rzs and Rzø independently from each other are selected from the group
consisting
of hydrogen and halogen;
R3 is hydrogen;
R4 is -CONHRS, -CHZCN, -CN or -NHR6;
R5 is hydrogen or Cl-C3-alkyl;
R6 is -CO-(Cl-C6)-alkyl or -SOz-(Cl-C6)-alkyl; and
n is 0, 1, 2 or 3;
as well as individual isomers, racemic or non-racemic mixtures thereof.
It has been found that the compounds of general formula I and I* as well as
individual
1o isomers, racemic or non-racemic mixtures thereof (hereinafter: Active
Compounds) are
selective monoamine oxidase B inhibitors.
Monoamine oxidase (MAO, EC 1.4.3.4) is a flavin-containing enzyme responsible
for the
oxidative deamination of endogenous monoamine neurotransmitters such as
dopamine,
serotonin, adrenaline, or noradrenal~ne, and trace amines, e.g. phenylethyl-
amine, as well
as a number of amine xenobiotics. The enzyme exists in two forms, MAO-A and
MAO-B,
encoded by different genes [Bach et al., Proc. Natl. Acad. Sci. USA 85:4934-
4938 (1988)]
and differing in tissue distribution, structure and substrate specificity. MAO-
A has higher
affinity for serotonin, octopamine, adrenaline, and noradrenaline; whereas the
natural
substrates for MAO-B are phenylethylamine and tyramine. Dopamine is thought to
be
oxidised by both isoforms. MAO-B is widely distributed in several organs
including brain
(Cesura and Pletscher, Prog. Drug Research 38:171-297 (1992)]. Brain MAO-B
activity
appears to increase with age. This increase has been attributed to the gliosis
associated with
aging [Fowler et al., J. Neural. Transm. 49:1-20 (1980)]. Additionally, MAO-B
activity is
significantly higher in the brains of patients with Alzheimer's disease
[Dostert et al., Bio-
chem. Pharmacol. 38:555-561 (1989)] and it has been found to be highly
expressed in
astrocytes around senile plaques [Saura et al., Neuroscience 70:755-774
(1994)]. In this
context, since oxidative deamination of primary monoamines by MAO produces
NH3,
aldehydes and HzOz, agents with established or potential toxicity, it is
suggested that there
is a rationale for the use of selective MAO-B inhibitors for the treatment of
dementia and
3o Parkinson's disease. Inhibition of MAO-B causes a reduction in the
enzymatic inactivation
of dopamine and thus prolongation of the availability of the neurotransmitter
in dopa-
minergic neurons. The degeneration processes associated with age and
Alzheimer's and
Parkinson's diseases may also be attributed to oxidative stress due to
increased MAO acti-
vity and consequent increased formation of HZOz by MAO-B. Therefore, MAO-B
inhibi-
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tors may act by both reducing the formation of oxygen radicals and elevating
the levels of
monoamines in the brain.
Given the implication of MAO-B in the neurological disorders mentioned above,
there is
considerable interest to obtain potent and selective inhibitors that would
permit control
over this enzymatic activity. The pharmacology of some known MAO-B inhibitors
is for
example discussed byBentue-Ferrer et al. [CNS Drugs 6:217-236 (1996)]. Whereas
a major
limitation of irreversible and non-selective MAO inhibitor activity is the
need to observe
dietary precautions due to the risk of inducing a hypertensive crisis when
dietary tyramine
is ingested, as well as the potential for interactions with other medications
[Gardner et al.,
1o J. Clin. Psychiatry 57:99-104 ( 1996)], these adverse events are of less
concern with rever-
sible and selective MAO inhibitors, in particular of MAO-B. Thus, there is a
need for
MAO-B inhibitors with a high selectivity and without the adverse side-effects
typical of
irreversible MAO inhibitors with low selectivity for the enzyme.
The following definitions of general terms used herein apply irrespective of
whether the
terms in question appear alone or in combination. It must be noted that, as
used in the
specification and the appended claims, the singular forms "a", "an," and "the"
include
plural forms unless the context clearly dictates otherwise.
The term "(Cl-C6)-alkyl" used in the present application denotes straight-
chain or
branched saturated hydrocarbon residues with 1 to 6 carbon atoms, such as
methyl, ethyl,
2o n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, and the like, preferably
with 1 to 3 carbon
atoms. Accordingly, the term "(Cl-C3)-alkyl" means a straight-chain or
branched saturated
hydrocarbon residue with 1 to 3 carbon atoms.
The term "halogen' denotes fluorine, chlorine, bromine and iodine.
"Halogen-(Cl-C6)-alkyl" or "halogen-(Cl-C6)-alkoxy" means the lower alkyl
residue or
lower alkoxy residue, respectively, as defined herein substituted in any
position with one
or more halogen atoms as defined herein. Examples of halogenalkyl residues
include, but
are not limited to, 1,2-difluoropropyl, 1,2-dichloropropyl, trifluoromethyl,
2,2,2-trifluoro-
ethyl, 2,2,2-trichloroethyl, and 3,3,3-trifluoropropyl,~and the like.
"Halogenalkoxy" in-
cludes trifluoromethyloxy.
3o "(Cl-C6)-Alkoxy" means the residue -O-R, wherein R is a lower alkyl residue
as defined
herein. Examples of alkoxy radicals include, but are not limited to, methoxy,
ethoxy, iso-
propoxy, and the like.
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"Pharmaceutically acceptable salts" of a compound means salts that are
pharmaceutically
acceptable, which are generally safe, non-toxic, and neither biologically nor
otherwise un-
desirable, and that possess the desired pharmacological activity of the parent
compound.
These salts are derived from an inorganic or organic acid or base. If
possible, compounds
of formula I may be converted into pharmaceutically acceptable salts. It
should be
understood that pharmaceutically acceptable salts are included in the present
invention.
In another embodiment the present invention provides compounds of formula I'~,
wherein
R3 is hydrogen and R4 is selected from the group consisting of -CONHRS, -
CHZCN, or
-CN.
1o Those compounds of formula I'~, wherein R4 is -CONHRS and R5 is hydrogen or
(Cl-C3)-
alkyl, axe especially preferred. Examples of such compounds are
(RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid
methylamide;
(RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid
amide;
(RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid
amide;
(RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid
methylamide;
(RS)-2-oxo-1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic
acid
amide; and
(RS)-2-oxo-1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic
acid
methylamide.
Another group of preferred compounds of formula I* are those, wherein R4 is -
CN. (RS)-
1-(4-benzyloxy-phenyl)-2-oxo-pyrrolidine-3-carbonitrile is an example of such
a
compound.
z5 Also preferred are compounds of formula I'~, wherein R3 is hydrogen, R4 is -
NHR6 and R6
is -CO-(C1-C6)-alkyl or -SOZ-(Cl-C&)-alkyl. Examples of such compounds are (S)-
N-[1-
(4-benzyloxy-phenyl)-2-oxo-pyrrolidin-3-yl]-acetamide and (S)-N-[1-(4-
benzyloxy-
phenyl)-2-oxo-pyrrolidin-3-yl] -methanesulfonamide.
Compounds of formula I* may be substituted by n Rl selected from the group
consisting
of halogen, halogen-(Cl-C6)-alkyl, cyano, (Cl-C6)-alkoxy or halogen-(Cl-C6)-
alkoxy,
wherein n denotes an integer selected from 0, 1, 2 and 3. Preferably n is 1 or
2. Preferred
compounds of formula I'~ are those, wherein Rl is halogen or halogen-(CI-C6)-
alkyl.
Especially preferred are those compounds of formula I*, wherein Rl is
fluorine, chlorine or
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trifluoromethyl. Where the compounds of formula I'~ are substituted by two or
three R1,
each Rl can be the same or different.
In one embodiment the invention provides compounds of formula I wherein -X-Y-
is
-CHZ-O-. In another embodiment the invention provides compounds of formula I
where-
in -X-Y- is -CHZ-CHZ- or -CH=CH-.
In one embodiment the invention provides compounds of formula I wherein Rl,
Rl'1 and
Rl'2 independently from each other are selected from the group consisting of
hydrogen
halogen, methyl, halogenmethyl, cyano, methoxy or halogen-methoxy. In another
embodi-
ment the present invention provides compounds of formula I wherein Rl, Rl'1
and Rl'2 are
l0 halogen, e.g. fluoro, e.g. 2,4,6-trifluoro, 2,4,5-trifluoro, 2,3,6-
trifluoro, 2,3,4-trifluoro or
3,4,5-trifluoro. In still another embodiment the present invention provides
compounds of
formula I wherein Rl'2 is hydrogen and Rl and Ri'1 independently from each
other are
selected from the group consisting of hydrogen, halogen, (Cl-C6)-alkyl,
halogen-(Cl-C6)-
alkyl, cyano, (Cl-C6)-alkoxy or halogen-(Cl-C6)-alkoxy. In still another
embodiment the
present invention provides compounds of formula I wherein Rl'Z is hydrogen and
Rl and
Rl'1 independently from each other are selected from the group consisting of
halogen and
(Cl-C6)-alkyl. In still another embodiment the present invention provides
compounds of
formula I wherein Rl'z is hydrogen, Rl'1 is halogen and Rl is halogen or (Cl-
C6)-alkyl. In
still another embodiment the present invention provides compounds of formula I
wherein
2o Rl'1 and Rl'2 are hydrogen and Rl is halogen, (Cl-C6)-alkyl, halogen-(Cl-
C6)-alkyl, cyano,
(Cl-C6)-alkoxy or halogen-(C1-C6)-alkoxy. In still another embodiment the
present inven-
tion provides compounds of formula I wherein Rl'I and Rl'Z are hydrogen and Rl
is halo-
gen, methyl, halogenmethyl, cyano, methoxy or halogen-methoxy. In still
another embodi-
ment the present invention provides compounds of formula I wherein Rl'I and
Rl'Z are
hydrogen and Rl is fluoro, e.g. 3-fluoro or 4-fluoro, chloro, e.g. 3-chloro,
halogenmethyl,
e.g. 3-trifluoromethyl or 4-trifluoromethyl, cyano, methoxy, e.g. 2-methoxy, 3-
methoxy or
4-methoxy, or halogen-methoxy, e.g. 3-trifluoromethoxy. In another embodiment
the
present invention provides compounds of formula I wherein Rl, Rl'1 and Rl'Z
are
hydrogen.
3o In one embodiment the present invention provides compounds of formula I
wherein RZia
R22 and R23 are hydrogen.
In one embodiment the present invention provides compounds of formula I
wherein Rz4 is
hydrogen.
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In one embodiment the present invention provides compounds of formula I
wherein R4 is
-CONHRS, wherein R5 is hydrogen or (Cl-C3)-alltyl. In another embodiment the
present
invention provides compounds of formula I wherein R4 is -CONHRS, wherein R5 is
hydrogen or methyl.
In one embodiment the present invention provides compounds of formula I
wherein R4 is
-CN.
In one embodiment the present invention provides compounds of formula I
wherein R4 is
-NHR6, wherein 8615 -CO-H, -CO-(Cl-C6)-alkyl, -CO-halogen-(Cl-C3)-alkyl, -CO-O-
(Cl-C3)-alkyl, -CO-NHz or -SOz-(Cl-C6)-alkyl. In another embodiment the
present
to invention provides compounds of formula I wherein R4 is -NHR6, wherein R6
is -CO-H, -
CO-(Cl-C6)-alkyl, -CO-O-(Cl-C3)-alkyl, -CO-NHz or -SOz-(Cl-C6)-alkyl. In still
another
embodiment the present invention provides compounds of formula I wherein R4 is
-
NHR6, wherein R6 is -CO-H, -CO-methyl, -CO-O-methyl, -CO-NHz or -SOz-methyl.
In one aspect the present invention provides compounds of formula I wherein
the
compounds have (S)-configuration. In one aspect the present invention provides
compounds of formula I wherein the compounds have (R)-configuration.
In one embodiment the present invention provides compounds of formula I
wherein X-Y
is -CHz-O-; Rl, Rl'1 and Rl'z independently from each other are selected from
the group
consisting of hydrogen, halogen, methyl, halogenmethyl, cyano, methoxy or
halogen-
2o methoxy; Rzl, Rzz and Rz3 are hydrogen; Rz4 is hydrogen and R4 is -CONHRS,
wherein R5
is hydrogen or (Cl-C3)-alkyl.
In one embodiment the present invention provides compounds of formula I
wherein X-Y
is -CHz-O-; Rl, Rl'1 and Rl'z independently from each other are selected from
the group
consisting of hydrogen, halogen, methyl, halogenmethyl, cyano, methoxy or
halogen-
methoxy; Rzl, Rzz and Rz3 are hydrogen; Rz4 is hydrogen and R4 is -CN.
In one embodiment the present invention provides compounds of formula I
wherein X-Y
is -CHz-O-; Rl, Rl'1 and Rl'z independently from each other are selected from
the group
consisting of hydrogen, halogen, methyl, halogenmethyl, cyano, methoxy or
halogen-
methoxy; Rzl, R22 and Rz3 are hydrogen; Rzø is hydrogen and R4 is -NHR6,
wherein R6 is -
3o CO-H, -CO-(Cl-C6)-alkyl, -CO-halogen-(Cl-C3)-alkyl, -CO-O-(Cl-C3)-alkyl, -
CO-NHz
or -SOz-(Cl-C6)-alkyl.
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In one embodiment the present invention provides compounds of formula I
wherein X-Y
is -CHz-O-; Rl'z is hydrogen and Rl and Rl'1 independently from each other are
selected
from the group consisting of hydrogen, halogen, (Cl-C6)-alkyl, halogen-(Cl-C6)-
alkyl,
cyano, (Cl-C6)-alkoxy or halogen-(Cl-C6)-alkoxy; Rzl, Rzz and Rz3 are
hydrogen; Rz4 is
hydrogen; and R4 is -CONHRS, wherein RS is hydrogen or (Cl-C3)-alkyl.
In one embodiment the present invention provides compounds of formula I
wherein X-Y
is -CHz-O-; Rl'1 and Rl'z are hydrogen and RI is halogen, (Cl-C6)-alkyl,
halogen-(Cl-C6)-
alkyl, cyano, (Cl-C6)-alkoxy or halogen-(Cl-C6)-alkoxy; Rzl, Rzz and Rz3 are
hydrogen; Rz4
is hydrogen; and R4 is -CONHRS, wherein R5 is hydrogen or (Cl-C3)-alkyl.
to In one embodiment the present invention provides compounds of formula I
wherein X-Y
is -CHz-O-; Rl, Rl'1 and Rl'z are hydrogen; Rzl, Rzz and Rz3 are hydrogen; Rz4
is hydrogen;
and R4 is -CONHRS, wherein RS is hydrogen or (Cl-C3)-alkyl.
In one embodiment the present invention provides compounds of formula I
wherein X-Y
is -CHz-O-; Rl'z is hydrogen and Ri and Ri'1 independently from each other are
selected
from the group consisting of hydrogen, halogen, (Ci-C6)-alkyl, halogen-(Cl-C6)-
alkyl,
cyano, (Cl-C6)-alkoxy or halogen-(Cl-C6)-alkoxy; Rzl, Rzz and Rz3 are
hydrogen; Rz4 is
hydrogen; and R4 is -CN.
In one embodiment the present invention provides compounds of formula I
wherein X-Y
is -CHz-O-; Rl'1 and Rl'z are hydrogen and RI is halogen, (Cl-C6)-alkyl,
halogen-(Cl-C6)-
2o alkyl, cyano, (Cl-C6)-alkoxy or halogen-(C1-C6)-alkoxy; Rzi, Rzz and Rz3
are hydrogen; Rz4
is hydrogen; and R4 is -CN.
In one embodiment the present invention provides compounds of formula I
wherein X-Y
is -CHz-O-; RI, Rl'1 and Rl'z are hydrogen; Rzl, Rzz and Rz3 are hydrogen; Rz4
is hydrogen;
and R4 is -CN.
z5 In one embodiment the present invention provides compounds of formula I
wherein X-Y
is -CHz-O-; Ri.z is hydrogen and Rl and Rl'1 independently from each other are
selected
from the group consisting of hydrogen, halogen, (Cl-C6)-alkyl, halogen-(Cl-C6)-
alkyl,
cyano, (Cl-C6)-alkoxy or halogen-(Cl-C6)-alkoxy; Rzl, Rzz and Rz3 are
hydrogen; Rz4 is
hydrogen; and R4 is -NHR6, wherein R6 is -CO-H, -CO-(Cl-C6)-alkyl, -CO-halogen-
(Cl-
so C3)-alkyl, -CO-O-(Cl-C3)-alkyl, -CO-NHz or -SOz-(Cl-C6)-alkyl.
In one embodiment the present invention provides compounds of formula I
wherein X-Y
is -CHz-O-; Rl'1 and Rl'z are hydrogen and Rl is halogen, (Cl-C6)-alkyl,
halogen-(Cl-C6)-
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alkyl, cyano, (C1-C6)-alkoxy or halogen-(C1-C6)-alkoxy; Rzl, Rzz and Rz3 are
hydrogen; Rz4
is hydrogen; and R4 is -NHR6, wherein R6 is -CO-H, -CO-(Cl-C6)-alkyl, -CO-
halogen-
(Cl-C3)-alkyl, -CO-O-(Cl-C3)-alkyl, -CO-NHz or -SOz-(Ci-C6)-alkyl.
In one embodiment the present invention provides compounds of formula I
wherein X-Y
is -CHz-O-; Rl, Rl'I and Rl'z are hydrogen; Rzl, Rzz and Rz3 are hydrogen; Rz4
is hydrogen;
and Rø is -NHR6, wherein R6 is -CO-H, -CO-(Cl-C6)-alkyl, -CO-halogen-(Cl-C3)-
alkyl, -
CO-O-(Cl-C3)-alkyl, -CO-NHz or -SOz-(Cl-C6)-alkyl.
In one embodiment the present invention provides compounds of formula I
wherein X-Y
is -CHz-O-; Rl'1 and Rl'z are hydrogen and Rl is halogen; Rzl, Rz2 and Rz3 are
hydrogen;
1o Rz4 is hydrogen; and R4 is -NHR6, wherein R6 is -CO-(Cl-C6)-alkyl. In
another embodi-
ment the present invention provides compounds of formula I wherein X-Y is -CHz-
O-;
Ri.y Ri.z~ Rzy Rzz~ R2s and Rz4 are hydrogen; Rl is halogen; and R4 is -NHR6,
wherein R6 is
-CO-methyl.
Examples of compounds of formula I include compounds selected from
15 (RS)-1-(4-benzyloxy-phenyl)-2-oxo-pyrrolidine-3-carbonitrile,
(RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid
methyl-
amide,
(RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid
amide,
(RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid
amide,
20 (RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-2-oxo-pyrxolidine-3-carboxylic acid
methyl-
amide,
(RS)-2-oxo-1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic
acid
amide,
(RS)-2-oxo-1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic
acid
25 methylamide,
(S)-N- [ 1-(4-benzyloxy-phenyl)-2-oxo-pyrrolidin-3-yl] -acetamide,
(S)-N- [ 1-(4-benzyloxy-phenyl)-2-oxo-pyrrolidin-3-yl] -methanesulfonamide,
(S)-N-{ 1-[4-(3-ffuoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-acetamide,
(R)-N-{ 1-[4-(3-ffuoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-acetamide,
30 (R)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-
methanesulfonamide,
(S)-N-{ 1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-
methanesulfonamide,
(S)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid
methyl
ester,
(R)-N-{ 1-[4-(3-ffuoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-formamide,
35 (S)-N-{1-[4-(3-ffuoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-formamide,
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(R)-{ 1- [4-(3-ffuoro-benzyloxy)-phenyl] -2-oxo-pyrrolidin-3-yl}-urea,
(S)-{ 1-[4-(3-ffuoro-benzyloxy)-phenylJ-2-oxo-pyrrolidin-3-yl}-urea,
(S)-N-{ 1-(S)- [4-(4-fluoro-benzyloxy)-phenyl] -2-oxo-pyrrolidin-3-yl}-
acetamide,
(S)-N-{1-(S)-[4-(2,6-diffuoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-
acetamide and
s (S)-N-{1-[4-(3,4-diffuoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-
acetamide.
In one embodiment the present invention provides a process for the preparation
of
compounds of formula I wherein
(a) R4 is CONHRS
comprising reacting a compound of formula II
Ra
Rzs
R24 / N~COOR*
R'''
R1 \ X~Y \ ~ R~z O (II)
~ / Ray
R'z
wherein R1, Rl.y Ri.z, Rzy R22~ Rzs~ Rz4~ Rs~ ~ and Y have the meanings as
defined above
and R'~ is hydrogen or (Cl-C6)-alkyl,
with an amine of formula HZN-R5, wherein R5 has the above meaning;
(b) R4 is CN
comprising reacting a compound of formula III
(III)
R
rc
wherein Rl, Rl.l, RI.zD Rzy Rzz, Rzs~ Rz4~ R3~ X and Y have the meanings as
defined above
and Hal is halogen,
with a cyanide salt; or
(c) R4 is NHR6
comprising reacting a compound of formula IV
(IV)
n
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wherein Rl, Rl'1, Ri.z, Rzi, Rzz~ Rzs~ Rz4~ R3~ X and Y have the meanings as
defined above,
with an acyl donating agent of formula Z-CO-(Cl-C6)-alkyl, Z-CO-halogen-(Cl-
C3)-alkyl,
Z-CO-O-(Cl-C3)-alkyl, or Z-SOz-(Cl-C3)-alkyl wherein Z is an activating group,
e.g. a
halogen or anhydride , or with an isocyanate.
The compounds of general formula I* can be manufactured by reacting a compound
of
formula II'~
Rz3 COOH
Rza N
\~//
~ R2~ o (II'~)
iR )n l /J Rzt
wherein Rl, Rzl, Rzz, R23' R24 and n have the above meanings
with an amine of formula H2N-R5, wherein R5 has the above meaning, to obtain a
1o compound of formula Ia*
Rz3 CONHRS
Rza / N \1
~o w I R22 0 (Ia*)
~Ri)n~ Rzt
or, alternatively, reducing a compound of formula II'~ to the corresponding
alcohol of
formula III'
Rz3 CHZOH
R
\ o ~ R22 0 (III')
~R )n l 'J Rzt
and reacting this compound with a cyanide salt to obtain a compound of formula
Ib*
Rz3 CH2CN
N
/
~o ~ R2z ° (Ib*)
~R )n l /J Rz,
or, alternatively,
reacting a compound of formula IV's
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R~ X
Rz4 N \\
~\ o \ ~ R22 ° (IV's)
~R )n l ') R2t
wherein X is halogen, with a cyanide salt, to obtain a compound of formula
Ic'~
Rz3 CN
Rza N
\~//
\ \ ~ ~ o (Ic'~)
~Rt)~~O Rzt R
or, alternatively, reacting a compound of formula V*
Rza NHz
Rza N
\~//
O \ ~ Rzz o
~Rt)~~ Rzt
with an acylating agent of formula Y-CO-(Cl-C6)-alkyl or Y'-SOZ-(Cl-C6)-alkyl,
wherein Y
and Y' represent an activating group, e.g. a halogen,
to obtain a compound of formula Id*
Rz3 ,~ NHR6
Rz4 N/.\ /
\ zz ° (Id's)
\
~Rt)~O Rzt R
to wherein R6 has the above meanings.
In accordance with the present invention, scheme 1 shows examplary routes to
com-
pounds of the formula I, all starting from a compound of formula V. The
reaction of a
compound of formula V with a compound of formula VI [Ikuta et al., J. Med.
Chem.
30:1995 (1987)] to obtain the intermediate of formula IIIa, may be in inert
solvents like
15 dichloromethane, ethyl acetate or ethers in the presence of a base like
triethylamine or
carbonate and at a temperature in the range of from 0°C to 25°C.
Cyclisation of the
intermediate 2,4-dihalo-N-acyl derivative to the pyrrolidone IIIa may be with
bases like
sodium or potassium hydroxide in inert solvents like dichloromethane or ethers
at a
temperature of from 0°C to 25°C. Intermediates II wherein R* is
H, i.e. compounds of
20 formula IIa, are prepared by reacting a compound of formula V with 6,6-
dimethyl-5,7-
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dioxa-spiro[2,5]octane-4,8-dione, as described by Danishefsky et al. [J.
Amer.Chem. Soc.
97:3239 (1975)].
Scheme 1
hal
I
Rz3 1) hal-CHZCHZ CHC~hal, z4 R~ ~
Rz4 NH VI II R / N~ hal
/ z O Ri.i I ~O
1.1
R \ X. \ I zz 1 ~\ X~Y \ Rzz
R1 Y z~ R 2) cyclisation R~ Rzi
' / R Ri.z
Ri'z V Illa
O
H3 R23
Rz4 N ~'~C
O CH3 1.1 / /'~~OH
O R X~ \ I zz O
V \
VII Ri Y Rz~ R Ila
Ri.z
Another method to prepare compounds of formula I involves cross-coupling
reactions of
arylstannanes [Lam et al., Tetrahedron Lett. 43:3091 (2002)], arylboronates
[Lam et al.,
Synlett 5:674 (2000); Chan et al., Tetrahedron Lett. 39:2933 (1998)] or aryl
halides [Buch-
wald et al., J. Amer. Chem. Soc. 118:7215 (1996)] with the corresponding
pyrrolidones
to (scheme 2).
Scheme 2
R3
R3
Rz3
R Rz3 L~ HN~ R Rza / N R4
/ ~'('O IX Ri.i I D
1.1 O
1R \ X~Y \ Rzz cat. ~ R' X Y \ z' Rzz
R Rzi t.z / R
Ri.z / VIII R I
wherein LG is halogen, e.g. Cl, Br or I, or SnR3 or B(OH)2.
In accordance with the present invention, a possibility to prepare compounds
of general
15 formula V, wherein -X-Y- is -CHZ-O-, i.e. compounds of formula Va, is shown
in scheme
3: The intermediates of formula XII are accessible through nucleophilic
substitution of
aromatic nitro compounds of formula XI containing p-substituted leaving groups
with
benzylic alcohols of formula X. Leaving groups in para-position can be, e.g.,
halogens (F,
Cl, Br, I), tosylates, mesylates or triflates. These substitution reactions
can be conducted
2o neat or in inert solvents like for example toluene or xylene. A preferred
reaction
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temperature is in the range of from 50°C to 150°C.
Alternatively, compounds of formula
XII can be prepared by Williamson-ether synthesis, starting from p-
nitrophenols XIV and
benzylic halides, tosylates, mesylates or triflates of formula XIII. Bases
used can be, e.g.
alcoholates or carbonates (sodium, potassium or cesium carbonate). Examples
for solvents
include lower alcohols, acetonitrile or lower ketones at a temperature in the
range of from
20°C to reflux temperature. Another approach is the Mitsunobu-coupling
of benzylic
alcohols with p-nitrophenols. The reaction is done as usual in inert solvents
like for
example diethyl ether or tetrahydrofurane, using dialkyl-azo-dicarboxylates in
the
presence of phosphines (for example tributyl- or triphenyl-phosphine).
to The key intermediates of formula XII are reduced to the amino compounds of
formula Va
using catalytic hydrogenation, like, e.g. using platinum on charcoal as the
catalyst in lower
alcohols, ethyl acetate or tetrahydrofurane. An alternative is the reduction
of the nitro-
group by metals like iron, tin, or zinc in acidic media like diluted
hydrochloric acid or
acetic acid. Metals can also be replaced by metal salts like, e.g., tin-(II)-
chloride).
Scheme 3
,.,
R''1 CH OH R I CH2LG
R
R
R,.~z /X + Rzs O R~.2 XIII
R24 Ras O+ R2a / N\O- +
/ ~O
LG ~ ~ R~ ~ ~HO \ z, R~x
2, Rzs O R XIV
XI R /
R,.,
~O ~ R~
R'
/ Ra,
R~,2 XII ~ Va
wherein LG is a leaving group, e.g. halogen and OTf, or OH (for Mitsunobu-
coupling).
In accordance with the present invention, a possibility to prepare the
intermediates of
formula Vb (wherein X-Y- is -CH=CH-) and Vc (wherein -X-Y- is -CHZ-CHZ-) is
2o shown in scheme 4: The intermediates of formula XVII are accessible by
olefination reac-
tion of optionally substituted aromatic aldehydes of formula XV with dialkyl
(4-nitro-
benzyl)-phosphonates of formula XVI in the presence of a base, like e.g.
sodium hydride,
yielding the corresponding nitro-olefins of formula XVII.
Scheme 4
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Rza O Rza O
Rw Rza N\ - Rza N\ -
CHO
R~ ~ / I O R~.~ ~ I O
\ Rzz --1 \ \ \ Rzz
~.z
R XV (alkyl0)zP(O) Rz' XVI R i.z ~ Rzi
R
XVII
Rza
Rza Rza NHz
Rz° / NHz Rte
R'.~ I . i \ \ \ ~ Rzz
\ \ Rzz ~ R Rzi
R~.z ~ Rz~ V~ Ri.z ~ Vb
The key intermediates of formula XVII can be reduced selectively to the amino-
olefins of
formula Vb using catalytic hydrogenation like e.g. using platinum on charcoal
as the cata-
lyst in lower alcohols, ethyl acetate or tetrahydrofurane as the solvent, or,
by metals or
metal salts, like e.g. tin-(II)-chloride. The amino derivatives of formula Vc
can be obtained
directly from the nitro derivatives of formula XVII or from the amino-olefins
of formula
Vb by hydrogenation using palladium on charcoal as the catalyst in lower
alcohols, ethyl
acetate or tetrahydrofurane as the solvent.
Intermediates II can be transformed into compounds of formula I using standard
to procedures. The acids II are activated via acid chloride (thionyl chloride
or oxalyl chloride)
or with DCC, EDC etc. and subsequently coupled with the amine R5-NH2.
Alternatively,
the corresponding alkylesters can be transformed to intermediates II by
aminolysis by
amines of formula R5-NHz.
Intermediates III can be transformed into the desired compounds I wherein R4
is CN, i.e.
15 compounds of formula Ib, by reaction with sodium or potassium cyanide in
solvents like
N,N-dimethylformamide, acetone or acetonitrile at a temperature in the range
of from
20°C to 140°C. Catalytic amounts of sodium or potassium iodide
can be added to speed up
the reaction (scheme 5).
Scheme 5
Rza
Rz< N~CN
20 III R,., \ X'Y \ ~ Rzz O Ib
R-[I'. Rz~
~/
R''z
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Compounds of formula IV can be obtained starting from acid derivatives of
formula II by
nucleophilic migrations from a carbon to a nitrogen atom, such as e.g. by
Hofmann or
Curtius rearrangement, via the formation of the corresponding isocyanate and
its treat-
ment with suitable alcohols delivering the protected amino group, methods
known per se
from the literature (scheme 6). For the treatment of the intermediate
isocyanate, alcohols
are selected which yield the typical carbamates used as amine protecting
groups, such as
e.g. tert-butoxycarbonyl, benzyloxycarbonyl, or fluorenylmethoxycarbonyl.
Their cleavage
to the amine follows the protocols which are well known in the literature. The
further
transformation to compounds of formula I can be performed by standard
procedures,
1o such as e.g. by reaction with activated acyl derivatives, e.g. acyl
halogenides or anhydrides,
or by condensation reactions of the acid using e.g. carbodiimides as
condensation reagent,
or by isocyanates.
Scheme 6
Rz3 NH-PG
Rza N
i.~ ~ IV
II R X~Y \ ~ Rzz G
R' Rzi
/ XVIII
R''
For the preparation of enantiopure derivatives of formula IV, an alternative
route can be
followed (scheme 7). Basically, the protocol follows the conditions described
by Freidinger
et al. [J. Org. Chem. 47:104-109 ( 1982)) where the aniline derivative of
formula V is acyla-
ted by an N-protected methionine derivative in its racemic or optically active
form by
standard conditions of condensation reactions to give compounds of formula
XIX.
2o Methylation with methyliodide or trimethyl-sulfonium or
trimethylsulfoxonium salts and
treatment of the resulting dimethyl-sulfonium salt with base, such~as e.g.
sodium hydride
or lithium or potassium bis(trimethylsilyl)amide, in solvents inert under
these conditions,
e.g. THF, dichloromethane or N,N-dimethylformamide, yield the cyclised N-
protected
product of formula XX. Another variation of this cyclisation procedure is
described in
EP 985,665 which refers to a process for the preparation of 3-amino-2-oxo-
pyrrolidines.
Scheme 7
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S.CH3
Rte,
Rza N
S.CH3 R~.1 ~ I NH-PG
V + ~ R~ ~ X~Y ~ RzzO ~ XX
.PG XIX
HOOC N Rz~
H Ri.z
Rz3 Rzs
za
Rza / N~NH-PG _ i.i R ~ N NHz
R~.i I ~ R X ~ I zz O
i ~ X~Y ~ Rzz O R' Y z~ R
R / Rz~ R IV
i.z
R~.z R
-X-Y- _ -CHz O-: ~ Rzs
hydrogenolysis Rza / N~NH-PG
XX ~ HO ~ I Rzz~O XXa
alkylation
Rz~
R~
Rza / N~NHR6 -X-Y-=-CHZ O-: Rz3
R''' I O hydrogenolysis Rza / N~NHR6
~X~Y \ R~ ~
~ ~ R~ Rz~ alkylation HO ~ Rzz O
Id
R~.z Rzi
In compounds of formula I or XX where -X-Y- has the meaning of -CHZ-O- , the
op-
tionally substituted benzyl residue can function as a transient group which
can be cleaved
by hydrogenolysis. The resulting phenols Id and XXa can then be re-alkylated
by a dif
ferent benzyl group under the aforementioned conditions. As known to those
skilled in the
art, this process is only possible on condition that R6 and PG are
representing groups that
are stable under the aforementioned reaction conditions for the hydrogenolysis
and
Io alkylation reaction.
Compounds of general formula I can also exist in optical pure form. There ist
the
possibility to start with enantiopure compounds from the chiral pool, like
e.g. (R)- or (S)-
methionine. In other cases, separation into antipodes can be affected
according methods
known per se, either preferably at an early stage of the synthesis starting
with compounds
of formula II by salt formation with an optically active amine such as, for
example, (+)- or
(-)-1-phenylethylamine and separation of the diastereomeric salts by
fractional
crystallisation or preferably by derivatisation with a chiral auxiliary
substance such as, for
example, (+)- or (-)-2-butanol, (+)- or (-)-1-phenylethanol, or (+)- or (-)-
menthol and
separation of the diastereomeric products by chromatography and/or
crystallisation and
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subsequent cleavage of the bond to the chiral auxiliary substance. In order to
determine
the absolute configuration of the pyrrolidinone derivative obtained, the pure
diastereo-
meric salts and derivatives can be analysed by conventional spectroscopic
methods, with
X-ray spectroscopy on single crystals being an especially suitable method.
The Active Compounds are, as already mentioned above, monoamine oxidase B
inhibitors
and can be used for the treatment or prevention of diseases in which MAO-B
inhibitors
might be beneficial. These include acute and chronic neurological disorders,
cognitive
disorders and memory deficits. Treatable neurological disorders are for
instance traumatic
or chronic degenerative processes of the nervous system, such as Alzheimer's
disease, other
1o types of dementia, minimal cognitive impairment or Parkinson's disease.
Other indica-
tions include psychiatric diseases such as depression, anxiety, panic attack,
social phobia,
schizophrenia, eating and metabolic disorders such as obesity, as well as the
prevention
and treatment of withdrawal syndromes induced by abuse of alcohol, nicotine
and other
addictive drugs. Other treatable indications may be peripheral neuropathy
caused by can-
cer chemotherapy (WO 97/33,572), reward deficiency syndrome (WO 01/34,172), or
the
treatment of multiple sclerosis (WO 96/40,095), and other neuroinffammatory
diseases.
The Active Compounds are especially useful for the treatment and prevention of
Alzheimer's disease and senile dementia.
The pharmacological activity of the compounds was tested using the following
method:
2o The cDNAs encoding human MAO-A and MAO-B were transiently transfected into
EBNA
cells using the procedure described by Schlaeger and Christensen
[Cytotechnology 15:1-13
( 1998)]. After transfection, cells were homogenised by means of a Polytron
homogenizer
in 20 mM Tris HCl buffer, pH 8.0, containing 0.5 mM EGTA and 0.5 mM
phenylmethane-
sulfonyl fluoride. Cell membranes were obtained by centrifugation at 45,000 x
g and, after
two rinsing steps with 20 mM Tris HCl buffer, pH 8.0, containing 0.5 mM EGTA,
mem-
branes were eventually re-suspended in the above buffer and aliquots stored at
-80°C until
use.
MAO-A and MAO-B enzymatic activity was assayed in 96-well-plates using a
spectro-
photometric assay adapted from the method described by Zhou and Panchuk-
Voloshina
[Analytical Biochemistry 253:169-174 ( 1997)]. Briefly, membrane aliquots were
incubated
in 0.1 M potassium phosphate buffer, pH 7.4, for 30 min at 37°C
containing different con-
centrations of the compounds. After this period, the enzymatic reaction was
started by the
addition of the MAO substrate tyramine together with 1 U/ml horse-radish
peroxidase
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(Roche Biochemicals) and 80 ~M N-acetyl-3,7-dihydroxyphenoxazine (Amplex Red,
Molecular Probes). The samples were further incubated for 30 min at
37°C in a final
volume of 200 ~.1 and absorbance was then determined at a wavelength of 570 nm
using a
SpectraMax plate reader (Molecular Devices). Background (non-specific)
absorbance was
determined in the presence of 10 ~M clorgyline for MAO-A or 10 ~M L-deprenyl
for
MAO-B. ICSO values were determined from inhibition curves obtained using nine
inhibitor
concentrations in duplicate, by fitting data to a four parameter logistic
equation using a
computer program.
The compounds of the present invention are specific MAO-B inhibitors. The ICSO
values of
to preferred Active Compounds as measured in the assay described above are in
the range of
1 ~M or less, typically 0.1 ~M or less, and ideally 0.02 ~.M or less.
The Active Compounds can be used as medicaments, e.g. in the form of
pharmaceutical
preparations. The pharmaceutical preparations can be administered orally, e.g.
in the form
of tablets, coated tablets, dragees, hard and soft gelatine capsules,
solutions, emulsions or
suspensions. However, the administration can also be effected rectally, e.g.
in the form of
suppositories, or parenterally, e.g. in the form of injection solutions.
The Active Compounds can be processed with pharmaceutically inert, inorganic
or
organic carriers for the production of pharmaceutical preparations. Lactose,
corn starch or
derivatives thereof, talc, stearic acid or its salts and the like can be used,
for example, as
2o such carriers for tablets, coated tablets, dragees and hard gelatine
capsules. Suitable carriers
for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-
solid and liquid
polyols and the like; depending on the nature of the active substance no
carriers are, how-
ever, usually required in the case of soft gelatine capsules. Suitable
carriers for the produc-
tion of solutions and syrups are, for example, water, polyols, sucrose, invert
sugar, glucose
and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils
and the like, can
be used for aqueous injection solutions of water-soluble salts of Active
Compounds, but as
a rule are not necessary. Suitable carriers for suppositories are, for
example, natural or
hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
In addition, the pharmaceutical preparations can contain preservatives,
solubilizers, stabi-
lizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts
for varying the
osmotic pressure, buffers, masking agents or antioxidants. They may also
contain other
therapeutically valuable substances.
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As mentioned earlier, medicaments containing an Active Compound and a
therapeutically
inert excipient are also an object of the. present invention, as is a process
for the pro-
duction of such medicaments which comprises bringing one or more Active
Compound
and, if desired, one or more other therapeutically valuable substances into a
galenical
dosage form together with one or more therapeutically inert carriers.
The dosage can vary within wide limits and will, of course, be fitted to the
individual
requirements in each particular case. In general, the effective dosage for
oral or parenteral
administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day
being
preferred for all of the indications described. The daily dosage for an adult
human being
to weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably
between 7 and
700 mg per day.
The following examples are provided for illustration of the invention. They
should not be
considered as limiting the scope of the invention, but merely as being
representative there-
of. The abbreviation "RT" means "room temperature".
Example 1: (RS)-1-(4-Benzyloxy-phenyl)-2-oxo-pyrrolidine-3-carbonitrile
a) (RS)-N-(4-Benzyloxy-phenyl)-2,4-dibromo-butyramide
A solution of 12.8 g (64.2 mmol) 4-benzyloxyaniline and 9.74 g (96.3 mmol)
triethylamine
in 125 ml dichloromethane is cooled to 0°C. 20.4 g (77.1 mmol) of 2,4-
dibromobutyryl
chloride [Ikuta et al., J. Med. Chem. 30:1995 (1987)] is slowly added over a
period of 45
2o min. The reaction mixture is stirred for additional 15 min, then hydrolysed
with 100 ml of
water. The insoluble precipitate is filtered off and the organic phase is
washed successively
with a saturated solution of sodium hydrogencarbonate and water. After drying
and eva-
poration, the crude product is subjected to chromatography (silica gel,
dichloromethane)
to yield 6.1 g (22 %) of a colorless solid. Mp = 139.5-142 °C.
b) (RS)-1-(4-Benzyloxy-phenyl)-3-bromo-pyrrolidin-2-one
6.1 g (14.3 mmol) (RS)-N-(4-benzyloxy-phenyl)-2,4-dibromo-butyramide and 0.1 g
of
Dowex 2X10 are suspended in 50 ml dichloromethane. 7 ml of a 50% aqueous
sodium
hydroxide solution is slowly added under vigorous stirring. The resulting
reaction mixture
is stirred overnight at RT, then poured into 25 ml of cold water. The organic
phase is
3o separated, dried and evaporated. The crude material is recrystallised from
ethyl acetate to
yield 1.72 g (35 %) of a brownish solid. Mp = 125-126 °C.
c) (RS)-1-(4-Benzyloxy-phenyl)-2-oxo-pyrrolidine-3-carbonitrile
300 mg (0.87 mmol) of (RS)-1-(4-benzyloxy-phenyl)-3-bromo-pyrrolidin-2-one is
dissolved in 5 ml N,N-dimethylformamide. 64 mg ( 1.3 mmol) sodium cyanide and
13 mg
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(0.09 mmol) sodium iodide are added and the suspension stirred for 10 min. at
120 °C.
The reaction mixture is treated with water and extracted with ethyl acetate to
yield 33 mg
( 13 %) of a colorless solid. MS: m/e = 293.3 (M+ H) +.
Example 2: (RS)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-
carboxylic
acid methylamide
a) 1-(4-Benzyloxy-phenyl)-pyrrolidin-2-one
20.3 g (101.9 mmol) 4-benzyloxyaniline and 9.1 ml (119.2 mmol) gamma-butyro-
lactone
are treated with 3m1 concentrated hydrochloric acid. The mixture is heated 20
hours to
160°C, then 5.5 hours to 200°C. After cooling, the mixture is
extracted with 250 ml ethyl
1o acetate, washed with saturated aqueous sodium hydrogencarbonate and dried.
Evapora-
tion of the solvent and recrystallisation from diethyl ether yields 8.4 g (31
%) of a
brownish solid. MS: m/e = 267 (M+).
b) 1-(4-Hydroxy-phenyl)-pyrrolidin-2-one
6.2 g (23.2 mmol) 1-(4-benzyloxy-phenyl)-pyrrolidin-2-one is dissolved in 200
ml THF. 3
15 drops of acetic acid are added and the solution is hydrogenated for 5 hours
at RT and nor-
mal pressure in presence of 0.62 g palladium 10 % on charcoal. Filtration and
concentra-
tion gives a semisolid material. Chromatography (silica gel, dichloromethane /
methanol
95 : 5) yields 2.73 g (66 %) of a brownish solid. MS: m/e = 175.9 (M-H).
c) 1-[4-(3-Fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one
2o A mixture of 2.73 g ( 15.4 mmol) of 1-(4-hydroxy-phenyl)-pyrrolidin-2-one,
3.2 g ( 16.9
mmol) of 3-fluorobenzylbromide and 4.26 g (31 mmol) of potassium carbonate in
100 ml
of 2-butanone is heated at 80°C for 18 hours. After cooling to RT, the
reaction mixture is
treated with water and ethyl acetate. The organic layer is separated, dried
over magnesium
sulfate and evaporated under reduced pressure. The solid residue is
crystallised from ether
25 to yield 3.86 g (88% of theory) of 1-[4-(3-fluoro-benzyloxy)-phenyl]-
pyrrolidin-2-one as
a colorless solid. MS: m/e = 286.0 (M+ H)+
d) 1-[4-(3-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid ethyl
ester
370 mg ( 15.4 mmol) sodium hydride is suspended in 20 ml THF and 911 mg (7.7
mmol)
diethylcarbonate is added. The suspension is heated to reflux temperature. A
solution of
3o 2.0 g (7.0 mmol) 1-[4-(3-Fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one in 10
ml THF is
slowly added into the boiling solution. The mixture is boiled for another 5
hours, then
hydrolysed with cold water and washed successively with water, saturated
sodium hydro-
gencarbonate solution, water and saturated sodium chloride solution.
Chromatography
(silica gel, dichloromethane / ethyl acetate) yields 1.3 g (52 %) of a
yellowish semisolid.
35 MS: m/e = 358.2 (M+ H)+.
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e) (RS)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid
methyl-
amide
300 mg (0.84 mmol) 1-[4-(3-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-
carboxylic
acid ethyl ester is dissolved in 2 ml N,N-dimethylformamide. 0.17 ml (4.2
mmol) of a 33 %
solution of methylamine in ethanol is added. The reaction vessel is tightly
stoppered and
heated to 120°C for 24 hours. Addition of water precipitates the crude
material. Chroma-
tography (silica gel, dichloromethane / methanol) yields 41 mg ( 14 %) of a
yellowish solid.
M5: m/e = 343.2 (M+ H)+.
Example 3: (RS)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-
carboxylic
1 o acid amide
a) 1-(3-Fluorobenzyloxy)-4-nitro-benzene
A mixture of 5.04 g (40 mmol) 3-fluorobenzyl alcohol and 1.29 g (4mmo1) tris-
(dioxa-3,6-
heptyl)amine is treated with 2.47 g (44 mmol) of potassium hydroxide. The
mixture is
stirred at RT for 10 min, then 5.55 g (44 mmol) of 4-fluoro-nitrobenzene is
slowly added
through a dropping funnel. The mixture is kept for 45 min at 80°C,
cooled to RT and di-
luted with about 75 ml water. Extraction with ethyl acetate and washing with
2M aqueous
hydrochloric acid yields a yellowish organic phase, which is dried and
evaporated. The
residue is recrystallised from methanol to give 6.07 g (61 %) of the title
compound. Yellow
crystals, mp = 104-105 °C.
2o b) 4-(3-Fluoro-benzyloxy)-phenylamine
3 g (12.1 mmol) of 1-(3-fluorobenzyloxy)-4-nitro-benzene is dissolved in 125
ml of
methanol. 150 mg of Pt 5% on charcoal is added and hydrogenation done under
normal
pressure for about 17 h. The catalyst is filtered and the solution evaporated
to yield 2.51 g
(95%) of crude brownish material. MS: m/e = 218.4 (M+H)+.
c) (RS)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid
A solution of 561 mg (2.6 mmol) 4-(3-fluoro-benzyloxy)-phenylamine and 448 mg
(2.6
mmol) 6,6-dimethyl-5,7-dioxa-spiro[2,5]octane-4,8-dione in 2ml dichloromethane
is
refluxed for 16 hours. 5 ml of diethylether is added and the precipitate
filtered off to yield
485 mg (57 %) of a colorless solid. MS: m/e = 330.2 (M+H)+.
3o d) (RS)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic
acid amide
300 mg (0.91 mmol) (RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-
carb-
oxylic acid is dissolved in 2 ml dichloromethane plus 2 drops of N,N-dimethyl-
formamide.
The solution is cooled to 0 °C and treated with 173 mg ( 1.37 mmol)
oxalyl chloride. After
1 hour at 0 °C the solvent is removed under vacuum at RT. The residue
is taken up in 1 ml
dichloromethane and slowly added to a mixture of 2 ml THF and 5 ml
concentrated
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_22_
ammonia. Stirring is continued for 1 hour at RT. Evaporation of the solvents
and dilution
with water yields a precipitate, which is filtered off. Recrystallisation from
methanol yields
112 mg (37 %) of a colorless solid. MS: m/e = 329.2 (M+H)+.
Example 4: (RS)-1-[4-(4-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-
carboxylic
acid amide
a) 1-(4-Fluorobenzyloxy)-4-nitro-benzene
The title compound is prepared in analogy to Example 3a) from 4-fluorobenzyl
alcohol
and 4-fluoro-nitrobenzene: Yield : 86 % of a yellowish solid. Mp = 124-
126°C.
b) 4-(4-Fluoro-benzyloxy)-phenylamine
to The title compound is prepared in analogy to Example 3b) by reduction of 1-
(4-fluoro
benzyloxy)-4-nitro-benzene. Yield : 98 % of a red solid. MS: m/e = 218.3
(M+H)+.
c) (RS)-1-[4-(4-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid
The title compound is prepared in analogy to Example 3c) from 4-(4-fluoro-
benzyloxy)-
phenylamine and 6,6-dimethyl-5,7-dioxa-spiro[2,5]octane-4,8-dione. Yield : 56
% of a
15 colorless solid. MS: m/e = 284.1 (M-CO2).
d) (RS)-1-[4-(4-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid
amide
The title compound is prepared in analogy to Example 3d) from (RS)-1-[4-(4-
fluoro-
benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid and ammonia. Yield :
18% of a
brownish solid. MS: m/e = 329.3 (M++ H).
2o Example 5: (RS)-1-[4-(4-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-
carboxylic
acid methylamide
The title compound is prepared in analogy to Example 3d) from (RS)-1-[4-(4-
fluoro-
benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid and methylamine. Yield
: 17% of
a colorless solid. MS: m/e = 343.2 (M+H)~.
25 Example 6: (RS)-2-Oxo-1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-
pyrrolidine-3-
carboxylic acid amide
a) 1-(4-Trifluoromethyl-benzyloxy)-4-nitro-benzene
The title compound is prepared in analogy to Example 3a) from 4-fluoro-nitro-
benzene
and 4-trifluoromethyl-benzyl alcohol. Yield 82 % of a slightly brown solid.
Mp. = 80.5 -
30 81.5 °C.
b) 4-(4-Trifluoromethyl-benzyloxy)-phenylamine
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The title compound is prepared in analogy to Example 3b) by reduction of 1-(4-
tri-
fluoromethyl-benzyloxy)-4-nitro-benzene. Yield : 91 % of a yellowish solid.
MS: m/e =
268.3 (M+H)+.
c) (RS)-2-Oxo-1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-pyrrolidine-3-
carboxylic acid
The title compound is prepared in analogy to Example 3c) from 4-(4-trifluoro-
methyl-
benzyloxy)-phenylamine and 6,6-dimethyl-5,7-dioxa-spiro[2,5]octane-4,8-dione.
Yield
37 % of a colorless solid. MS: m/e = 380.1 (M+H)+.
d) (RS)-2-Oxo-1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-pyrrolidine-3-
carboxylic acid
amide
150 mg (0.4 mmol) (RS)-2-oxo-1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-
pyrrolidine-
3-carboxylic acid. is dissolved in 4 ml THF. 59 mg (0.43 mmol) of 1-
hydroxybenzotriazole
and 80 mg (0.42 mmol) of N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide-hydro-
chloride is added and the reaction mixture is stirred at RT for 30 min. After
cooling to 0°C
4m1 of concentrated ammonia is added and the resulting mixture stirred at RT
for 1 hour.
Dilution with water, extraction and chromatography (silica gel, ethyl acetate)
yields 15 mg
(10 %) of a colorless solid. MS: m/e = 379.2 (M+H)+.
Example 7: (RS)-2-Oxo-1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-pyrrolidine-3-
carboxylic acid methylamide
The title compound is prepared in analogy to Example 6d) from (RS)-2-oxo-1-[4-
(4-
2o trifluoromethyl-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid and
methylamine.
Yield: 6 % of a colorless solid. MS: m/e = 393.2 (M+H)+.
Example 8: (S)-N-[1-(4-Benzyloxy-phenyl)-2-oxo-pyrrolidin-3-yl]-acetamide
a) (S)-[1-(4-Benzyloxy-phenylcarbamoyl)-3-methylsulfanyl-propyl]-carbamic acid
tert-
butyl ester
A solution of 0.57 g (2.3 mmol) of (S)-Boc-methionine in 5 ml of
dichloromethane is
treated at RT consecutively with 0.87 g (2.3 mmol) of O-(benzotriazol-1-yl)-
N,N,N',N'-
tetramethyluronium-hexafluorophosphate (HBTU), 0.50 g (2.1 mmol) of 4-
benzyloxy-
aniline hydrochloride and 0.98 ml (5.7 mmol) of N-ethyl-diisopropylamine. The
reaction
mixture is stirred during 1 h at RT. For the working-up, the reaction mixture
is diluted
3o with dichloromethane and treated with 20 ml of an aqueous solution of
citric acid ( 10%).
The aqueous phase is re-extracted with dichloromethane, the organic phases
combined,
dried over sodium sulfate and evaporated under reduced pressure. For
purification, the
crude material obtained is chromatographed on silica gel using a 3:1 mixture
of n-hexane
and ethyl acetate as the eluent. There are obtained 0.74 g (82.5% of theory)
of (S)-[1-(4-
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benzyloxy-phenylcarbamoyl)-3-methylsulfanyl-propyl]-carbamic acid tert-butyl
ester as a
white solid. MS: m/e = 431 (M+H)+.
b) (S)-[1-(4-Benzyloxy-phenyl)-2-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl
ester
A mixture of 0.35 g (0.81 mmol) of (S)-[1-(4-benzyloxy-phenylcarbamoyl)-3-
methyl-
sulfanyl-propyl]-carbamic acid tert-butyl ester and 8.79 g (62.0 mmol) of
methyliodide is
stirred at. RT for 3 d. Thereafter, the methyliodide is evaporated, the
intermediate sulf
onium salt dissolved in 15 ml of THF and treated with 0.79 ml (0.79 ml) of
lithium bis-
(trimethylsilyl)amide ( 1 M solution in THF) at 0°C. After stirring at
0°C for 2 h, the
reaction mixture is evaporated under reduced pressure and the solid residue is
directly
1o submitted to chromatography on silica gel using a 2:1 mixture of n-hexane
and ethyl
acetate as the eluent. There are obtained 0.175 mg (56% of theory) of (S)-[1-
(4-benzyloxy-
phenyl)-2-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl ester as a white
solid. MS: m/e =
383 (M+H)+.
c) (S)-3-Amino-1-(4-benzyloxy-phenyl)-pyrrolidin-2-one hydrochloride
A solution of 137 mg (0.36 mmol) of (S)-[1-(4-benzyloxy-phenyl)-2-oxo-
pyrrolidin-3-yl]-
carbamic acid tert-butyl ester in 2 ml of dioxane is treated with 0.3 ml of
hydrochloric acid
(37%). The solution is warmed to 45°C for 1 h forming a white
suspension. For the work-
ing-up, the reaction mixture is evaporated under reduced pressure and the
solid residue is
triturated with a small volume of methanol. After filtration and drying, 94 mg
of (S)-3-
2o amino-1-(4-benzyloxy-phenyl)-pyrrolidin-2-one hydrochloride (82% of theory)
are ob-
tamed as a white solid. MS: m/e = 283 (M + H)+.
d) (S)-N-[1-(4-Benzyloxy-phenyl)-2-oxo-pyrrolidin-3-yl]-acetamide
A solution of 40 mg (0.13 mmol) of (S)-3-amino-1-(4-benzyloxy-phenyl)-
pyrrolidin-2-
one hydrochloride in 2 ml of dichloromethane is treated with 38 ~1 (0.28 mmol)
of tri-
ethylamine and cooled to 0°C. To this solution, 10 ~1 (0.14 mmol) of
acetylchloride are
added and stirring at 0°C is continued for 30 min. For the working-up,
the reaction mix-
ture is treated with 2 ml of ammonium hydroxide solution, the organic phase
separated,
thereafter dried over sodium sulfate and evaporated under reduced pressure.
For purifi-
cation, the material obtained is chromatographed on silica gel using a 95:5
mixture of di-
3o chloromethane and methanol as the eluent. There are obtained 31 mg (76% of
theory) of
(S)-N-[1-(4-enzyloxy-phenyl)-2-oxo-pyrrolidin-3-yl]-acetamide as a white
solid. MS: m/e
= 325 (M+H)+.
Example 9: (S)-N-[1-(4-Benzyloxy-phenyl)-2-oxo-pyrrolidin-3-yl]-methanesulfon-
amide
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In an anologous manner to that described in Example 8d), the reaction of (S)-3-
amino-1-
(4-benzyloxy-phenyl)-pyrrolidin-2-one hydrochloride. with methanesulfochloride
in the
presence oftriethylamineyields (S)-N-[1-(4-benzyloxy-phenyl)-2-oxo-pyrrolidin-
3-yl]-
methanesulfonamide as a white solid. MS: m/e = 361 (M+H)+.
Example 10: (S)-N-{1-(4-(3-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-
acetamide
a) In an anologous manner to that described in Example 8a) to c), the (S)-3-
amino-1-[4-
(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride is obtained:
Condensation of (S)-BOC-methionine and 4-(3-fluorobenzyloxy)-phenylamine
[Example
3b)] by HBTU yields the (S)-{ 1-[4-(3-fluoro-benzyloxy)-phenylcarbamoyl]-3-
methylsulfanyl-propyl}-carbamic acid tert-butyl ester as a light yellow solid;
MS: m/e =
449 (M+H)+. The following methylation and cyclisation yields the (S)-{ 1-[4-(3-
fluoro-
benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester as a
white solid;
MS: m/e = 401 (M+H)+. The cleavage of the BOC-group yields the (S)-3-amino-1-
[4-(3-
fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride as a white solid; MS:
m/e =
301 (M+H)+.
b) ~S)-N-{ 1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-acetamide
In an anologous manner to that described in Example 8d), the acetylation of
the (S)-3-
amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride yields
the title
2o compound as a white solid; MS: m/e = 343 (M+H)~.
Example 11: (R)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-
acetamide,
(R)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-
methanesulfonamide,
(S)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-
methanesulfonamide and
(S)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-carbamic
acid methyl ester
In an anologous manner to that described in Example 8 d), the acylation of (R)-
or (S)-3-
3o amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride [the
(R)-
isomer is obtained in analogy to the (S)-isomer as described in Example 10 a)
starting
from (R)-BOC-methionine] yield the following compounds:
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a) Reaction of the (R)-3-amino-1-[4-(3-Iluoro-benzyloxy)-phenyl]-pyrrolidin-2-
one
hydrochloride with acetylchloride yields the (R)-N-{1-[4-(3-ffuoro- benzyloxy)-
phenyl]-2-
oxo-pyrrolidin-3-yl}-acetamide as a white solid; MS: m/e = 343 (M+H)+.
b) Reaction of the (R)-3-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-
one
hydrochloride with methanesulfochloride yields the (R)-N-{1-[4-(3-ffuoro-
benzyloxy)
phenyl]-2-oxo-pyrrolidin-3-yl}-methanesulfonamide as a white solid; MS: m/e =
377
(M+H)+.
c) Reaction of the (S)-3-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-
one
hydrochloride with methanesulfochloride yields the (S)-N-{ 1-[4-(3-fluoro-
benzyloxy)-
to phenyl]-2-oxo-pyrrolidin-3-yl}-methanesulfonamide as a white solid; MS: m/e
= 377
(M+H)+.
d) Reaction of the (S)-3-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-
one
hydrochloride with methyl chloroformate yields the (S)-{ 1-[4-(3-fluoro-
benzyloxy)-
phenyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid methyl ester as a white solid;
MS: m/e = 359
~5 (M+H)+.
Example 12 : (R)-N-{1-[4-(3-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-
formamide
A mixture of 188 mg ( 18 mmol) of acetic anhydride and 107 mg (23 mmol) of
formic acid
is prepared at 0°C, thereafter, heated to 60°C for 2 hours.After
cooling to RT, the mixture
2o is diluted with 1 ml of tetrahydrofurane and a solution of 213 mg (7 mmol)
of (R)-3-
amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one in 2 ml of
dichloromethane,
beforehand prepared from the corresponding hydrochloride by treatment with
triethylamine, is added. After the addition a white suspension is formed which
is stirred at
RT for 1 hour. For the working-up, the reaction mixture is treated with
dichloromethane
25 and water, then, the organic layer is separated, dried over sodium sulfate
and evaporated.
There are obtained 215 mg (92% of theory) of (R)-N-{ 1-[4-(3-Fluoro-benzyloxy)-
phenyl]-2-oxo-pyrrolidin-3-yl}-formamide as a white solid; MS: m/e = 329
(M+H)+.
Example 13 : (S)-N-{1-[4-(3-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-
formamide
3o In an analogous manner to that described in Example 12, the reaction of (S)-
3-amino-1-
[4-(3-ffuoro-benzyloxy)-phenyl]-pyrrolidin-2-one with a mixture of acetic
anhydride and
formic acid yields the title compound as a white solid; MS: m/e = 329 (M+H)+.
Example 14 : (R)-{1-[4-(3-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-
urea
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A solution of 250 mg (0.7 mmol) of (R)-3-amino-1-[4-(3-fluoro-benzyloxy)-
phenyl]-
pyrrolidin-2-one hydrochloride and 294 mg (2.2 mmol) of N-ethyl-
diisopropylamine in 2
ml of N,N-dimethylformamide is cooled to 0°C and treated with 267 mg
(2.2 mol) of
trimethylisocyanate. The reaction mixture is left to warm to RT and stirring
is continued
for 2 days. For the working-up, the suspension is evaporated under reduced
pressure. The
crude product is triturated in water, then the recovered solid material
triturated a second
time in a mixture of ethyl acetate and a saturated solution of sodium
hydrogencarbonate.
The remaining solid is collected on a filter funnel to give, after drying
under high vacuum,
155 mg (61% of theory) of (R)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-
pyrrolidin-3-
1o yl}-urea as a white solid; MS: m/e = 344 (M+H)+.
Example 15 : (S)-{1-[4-(3-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-
urea
In an analogous manner to that described in Example 14, the reaction of (S)-3-
amino-1-
[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one trimethylisocyanate yields
the title
compound as a white solid; MS: m/e = 344 (M+H)+.
Example 16 : (S)-N-{1-(S)-[4-(4-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-
yl}-
acetamide
a) (S)-[1-(4-Hydroxy-phenyl)-2-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl
ester
In an analogous manner to that described in Example 2b), the hydrogenolysis of
the. (S)-
[1-(4-benzyloxy-phenyl)-2-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl ester
[Example 8
2o b)] using palladium on carbon as the catalyst yields the title compound as
a white solid in
quantitative yield; MS: m/e= 291 (M-H)+.
b) (S)-{1-[4-(4-Fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid
tert-
butyl ester
In an analogous manner to that described in Example 2c), the alkylation of the
(S)-[1-(4-
hydroxy-phenyl)-2-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl ester with 4-
fluorobenzylbromide in presence of potassium carbonate yields the title
compound as a
white solid; MS: m/e= 401 (M+H)+.
c) (S)-3-Amino-1-[4-(4-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one
hydrochloride
In an analogous manner to that described in Example 8c), the cleavage of the
BOC-group
of the (S)-{ 1-[4-(4-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-carbamic
acid tert-
butyl ester yields the title compound as a white solid; MS: m/e= 301 (M+H)+.
d) (S)-N-{1-[4-(4-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-acetamide
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In an anologous manner to that described in Example ~ d), the acetylation of
the (S)-3-
amino-1-[4-(4-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride yields
the title
compound as a white solid; MS: m/e = 343 (M+H)+.
Example 17 : (S)-N-{1-(S)-[4-(2,6-Difluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-
3-yl}-
acetamide
a) (S)-{1-[4-(2,6-Difluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-carbamic
acid tert-
butyl ester
In an analogous manner to that described in Example 2c), the alkylation of the
(S)-[ 1-(4-
hydroxy-phenyl)-2-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl ester [Example
16 a)]
1o with 2,6-difluorobenzylbromide in presence of potassium carbonate yields
the title
compound as a white solid; MS: m/e= 419 (M+H)+.
b) (S)-3-Amino-1-[4-(2,6-difluoro-benzyloxy)-phenyl]-pyrrolidin-2-one
hydrochloride
In an analogous manner to that described in Example 8c), the cleavage of the
BOC-group
ofthe (S)-{1-[4-(2,6-difluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-
carbamic acid
15 tert-butyl ester yields the title compound as a white solid.
c) (S)-N-{1-[4-(2,6-difluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-
acetamide
In an anologous manner to that described in Example 8 d), the acetylation of
the (S)-3-
amino-1-[4-(2,6-difluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride
yields the
title compound as a white solid; MS: m/e = 361 (M+H)+.
2o Example 18 : (S)-N-{1-[4-(3,4-Difluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-
3-yl}-
acetamide
a) (S)-{1-[4-(3,4 -Difluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-carbamic
acid tert-
butyl ester
In an analogous manner to that described in Example 2c), the alkylation of the
(S)-[1-(4-
25 hydroxy-phenyl)-2-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl ester
[Example 16 a)]
with 3,4-difluorobenzylbromide in presence of potassium carbonate yields the
title
compound as a white solid; MS: m/e= 419 (M+H)''-.
b) (S)-3-Amino-1-[4-(3,4-difluoro-benzyloxy)-phenyl]-pyrrolidin-2-one
hydrochloride
In an analogous manner to that described in Example 8c), the cleavage of the
BOC-group
30 of the (S)-{1-[4-(3,4-difluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-
carbamic acid
tert-butyl ester yields the title compound as a white solid; MS : m/e= 319
(M+H)+.
c) (S)-N-{1-[4-(3,4-difluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-
acetamide
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In an anologous manner to that described in Example 8 d), the acetylation of
the (S)-3-
amino-1-[4-(3,4-difluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride
yields the
title compound as a white solid; MS: m/e = 361 (M+H)+.
Example A: Tablets
Tablets of the following composition are produced in a conventional manner:
mg/Tablet
Active ingredient 100
Powdered lactose 95
White corn starch 35
to Polyvinylpyrrolidone8
Na carboxymethylstarch 10
Magnesium stearate 2
Tablet weight 250
Example B: Tablets
Tablets of the following composition are produced in a conventional manner:
mg/Tablet
Active ingredient 200
Powdered lactose 100
White corn starch 64
2o Polyvinylpyrrolidone12
Na carboxymethylstarch 20
Magnesium stearate 4
Tablet weight 400
Example C: Capsules
Capsules of the following composition are produced:
mg/Capsule
Active ingredient 50
Crystalline lactose 60
Microcrystalline cellulose 34
3o Talc 5
Magnesium stearate 1
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Capsule fill weight 150
The active ingredient having a suitable particle size, the crystalline lactose
and the micro-
crystalline cellulose are homogeneously mixed with one another, sieved and
thereafter talc
and magnesium stearate are admixed. The final mixture is filled into hard
gelatine capsules
of suitable size.
Example D: Injection solution
An injection solution may have the following composition and is manufactured
in usual
manner:
Active substance 1.0 mg
io 1 N HCl 20.0 ~.l
acetic acid 0.5 mg
NaCI 8.0 mg
phenol 10.0 mg
1 N NaOH q.s. ad pH 5
HZO q.s. ad 1 ml
